This invention relates to bioadhesive compositions, particularly wound dressings comprising hydrogel compositions having bioadhesive properties.
One form of wound dressing commonly used comprises a perforated carrier material and a layer of hydrophilic coating which lies against the wound or sore. U.S. Pat. No. 5,352,508 (Cheong) discloses a net dressing in which the net is encapsulated by a hydrophilic tacky resin and wherein the resin encapsulated on the net leaves the majority of the apertures in the net substrate unoccluded. The hydrophilic tacky resin used as the coating is said to be a polymerised hydrogel.
An important feature for a wound dressing is that it should not adhere to the wound. This is in order that it is allowed to heal and to prevent damage to the wound on removal of the dressing. At the same time the wound dressing needs to adhere strongly to normal skin to prevent the wound dressing from coming off. Whilst it has been appreciated in the past that these features are important, there has been no understanding of how to achieve them in a hydrogel system.
It is an object of this invention to provide hydrogel skin adhesives possessing controlled and predictable adhesive properties which may be readily varied to suit different uses and, in the case of wound dressings or similar devices, different configurations or applications. It is also an object of the invention to provide such hydrogel skin adhesives which in addition may possess superior adhesion characteristics as compared to those commonly associated with bioadhesive hydrogels.
The performance of hydrogels as adhesives is related to the surface energetics of the adhesive and of the adherend (for example mammalian skin) and to the viscoelastic response of the bulk adhesive. The requirement that the adhesive wets the adherend to maximise the work of adhesion is well known. This requirement is generally met when the adhesive has a similar or lower surface energy to the adherend. The viscoelastic properties, in particular the elastic or storage modulus (Gxe2x80x2) and the viscosity modulus (Gxe2x80x3) are important. They are measured by dynamic mechanical testing at different rad/s. Their values at low rad/s (approximately 0.01 to Irad/s) and high rad/s (100 to 1000 rad/s) has been related to the wetting/creep behaviour and peel/quick stick properties respectively. The choice, assembly and processing of the ingredients of the hydrogel adhesive are usually targetted at making a material with a balance of properties suitable for pressure sensitive adhesive applications. A balance between the quantities and nature of polymer, plasticiser and the degree of crosslinking/entanglement has to be achieved.
Whilst the presence of glycerol or other polyhydric alcohols in other reported formulations has been quoted to provide humectant properties to the hydrogel, it has been found that the most important parameter to preventing water loss is the activity of the water within the hydrogel which in turn depends on the nature and proportions of the other components and manner of processing.
Water activity in the hydrogel adhesive is primarily dependent on the water content and the nature of the polymeric components and the way in which they are processed. Water activity has been shown to have a better correlation with the growth of bacteria and moulds than water content. It has been found that organisms struggle to grow at water activities less than 0.8. Enzyme activity has also been reported to decrease significantly below activity of 0.8. Some wound dressings currently available not only have high water contents but also high water activity, greater than 0.99. Although these materials are sterilised, on opening the pack they may become subject to encouraging microbial growth. Water activity has also been found to influence the adhesivity of the hydrogel adhesive in that at water activities above about 0.75, they become less adhesive. A bioadhesive composition having a suitable balance of the characteristics discussed above has now surprisingly been found.
According to the invention there is provided a water unstable bioadhesive composition characterised in that it has:
(i) a water activity of from 0.4 to 0.9;
(ii) an elastic modulus at 1 rad/s of from 700 to 15,000 Pa;
(iii) an elastic modulus at 100 rad/s of from 2000 to 40,000 Pa;
(iv) a viscous modulus at 1 rad/s of from 400 to 14,000 Pa;
(v) a viscous modulus at 100 rad/s of from 1000 to 35,000 Pa;
wherein the viscous modulus is less than the elastic modulus in the frequency range of from 1 to 100 rad/s. Preferably the surface energetics of the composition is from 25 to 40 dynes.
Examination of the rheological properties of the compositions have been successfully used to characterise and differentiate adhesive behaviour. Typically the elastic modulus (Gxe2x80x2) and the viscous modulus (Gxe2x80x3) are measured over a range of 0.01-100 rad/s at a given temperature. For skin applications the appropriate temperature is 37xc2x0 C. The moduli at low rad/s values relate to the initial bonding of the adhesive to skin and the higher to the changes in moduli values associated with de-bonding. Methods of measuring Gxe2x80x2 and Gxe2x80x3 are well known; for example a Rheometric Scientific RS-5 rheometer could be used.
The water activity of the composition can be measured using impedance methods with devices such as the Rotronic AWVC (manufactured by Rotronic). The activity of water may also be determined by placing the composition in environments of controlled humidity and temperature and measuring the changes in weight. The relative humidity (RH) at which the composition does not change weight corresponds to the activity of water in the gel (RH/100). The use of saturated salt solutions to provide the appropriate environmental conditions is well known. All compositions directly exposed to relative humidities less than that corresponding to the activity of water will be thermodynamically allowed to lose water. Exposure to greater relative humidities and the composition will gain weight.
The bioadhesive composition preferably comprises an aqueous plasticiser, a copolymer of a hydrophilic unsaturated water-soluble first monomer and a hydrophilic unsaturated water-soluble second monomer and a cross-linking agent, the first monomer having a tendency preferentially to enhance the bioadhesive properties of the composition.
Preferably the first monomer has a tendency also to enhance the mechanical strength of the composition according to the invention and/or the second monomer has a tendency preferentially to increase the water activity of the composition.
The bioadhesive composition is preferably obtainable by polymerising an aqueous reactive mixture comprising the said first monomer, the said second monomer and a crosslinking agent.
According to the invention, there is further provided a wound dressing which comprises a carrier material and the bioadhesive composition according to the invention. The carrier material is either encapsulated or coated by either of the bioadhesive compositions. Preferably it is coated, particularly on only one side.
According to the invention there is also provided a process for the preparation of a wound dressing according to the invention which process comprises either:
(a) coating or encapsulating a carrier material with an aqueous reaction mixture comprising the said first monomer, the said second monomer and a crosslinking agent, and curing the coating on the material; or
(b) coating a carrier material with the bioadhesive composition according to the invention.
In preferred embodiments the first and second monomers will be acrylate based monomers selected for their ability to polymerise rapidly in water and having substantially the same molecular weight whereby in a mixture of the two the relative proportions may be varied without significantly altering the molar characteristics of the composition.
The first monomer is preferably a compound of formula 
wherein R1 is an optionally substituted hydrocarbon moiety, R2 is hydrogen or optionally substituted methyl and ethyl, and M represents hydrogen or a cation.
R1 is preferably an optionally substituted alkyl, cycloalkyl or aromatic moiety. Preferably R1 represents a saturated moiety or an aromatic moiety. R1 preferably contains from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. A preferred moiety which R1 represents is 
wherein R3 represents hydrogen or an optionally substituted straight or branched chain alkyl group possessing from 1 to 6 carbon atoms and R4 represents an optionally substituted straight or branched chain alkyl group possessing from 1 to 6 carbon atoms.
The second monomer is preferably a compound of formula 
wherein R5 represents hydrogen or optionally substituted methyl or ethyl, R6 represents hydrogen, a cation or R7SO3 wherein R7 represents an optionally substituted alkylene moiety of 1 to 4 carbon atoms. Preferably R7 represents optionally substituted n-propyl.
R1, R2, R3, R4, R5 and R7 are optionally substituted by a group which preferably has a tendency to increase the water solubility of the compound. Suitable groups will be well known to a person of skill in the art. A preferred optional substituent is a hydroxyl, amino or ammonium group or a halogen (e.g. chlorine, bromine, or iodine) atom. A suitable cation is an alkali metal cation, especially sodium or potassium.
Most preferably the first monomer is 2-acrylamido-2-methylpropanesulphonic acid or an analogue thereof or one of its salts, e.g. an alkali metal salt such as a sodium, potassium or lithium salt. The second monomer preferably is acrylic acid or an analogue thereof or one of its salts, e.g. an alkali metal salt such as sodium, potassium or lithium or it preferably is a polymerisable sulphonate or a salt, e.g. an alkali metal salt such as a sodium, potassium or lithium salt, of acrylic acid (3-sulphopropyl)ester or an analogue thereof. Particular preferred examples of these respective monomers are the sodium salt of 2-acrylamido-2-methylpropanesulphonic acid, commonly known as NaAMPS, and acrylic acid (3-sulphopropyl)ester potassium salt, commonly known as SPA. NaAMPS is available commercially at present from Lubrizol as either a 50% aqueous solution (reference code LZ2405) or a 58% aqueous solution (reference code LZ2405A). SPA is available commercially in the form of a solid from Raschig.
The total monomer content in the aqueous reactive mixture is preferably from 15% to 60% by weight, preferably from 20% to 50% by weight.
One advantage of the bioadhesives and wound dressings according to the present invention is that they do not adhere to wet skin. This is measured by the decrease in peel strength of a hydrogel when it absorbs water, for example more than 3% by weight water. It has been found that this decrease in peel strength is optimal for certain weight ratios of monomers. A further advantage of the composition according to the invention is that tests have shown that such compositions are readily sterilisable. Consequently they have particular application in products having medical uses, such as wound dressings.
Where the first monomer is a salt of AMPS and the second monomer is a salt of acrylic acid, the ratio by weight of the first monomer to the second monomer is preferably not less than 2:1 and preferably not less than 3:1. Where the first monomer is a salt of AMPS and the second monomer is a salt of acrylic acid (3-sulphopropyl)ester, the ratio by weight of the first monomer to the second monomer is preferably not less than 1:10, preferably not less than 1:1.
The first monomer is preferably included in an amount by weight of from 1% to 60%, more preferably from 5% to 50%, most preferably from 15% to 40%. The second monomer is preferably included in an amount by weight of from 1% to 50%, preferably from 10% to 30%, most preferably from 10% to 20%. The crosslinker is preferably included in an amount of from 0.01% to 2%, more preferably from 0.1 to 2% by weight. The balance of the composition preferably comprises an aqueous plasticiser.
One advantage of the first and second monomers is that it has been found that high monomer content solutions can be achieved (approximately 75%). It has also been found that the second monomer is soluble in polyhydric alcohols such as glycerol, and addition of glycerol to the first and second monomer mixture enhances the solubilisation process. It has been found that the combination of the two monomers enables a greater control over water content than can be achieved otherwise. This can be important because it has also been found that compositions made with the final water content as an integral part of the pre-gel mix have different properties from those made with an excess of water and then dried to the final composition. For example, hydrogels with a final composition obtained be the evaporation of water generally have lower elastic or storage moduli than those made with no evaporation of water. To obtain similar levels of elastic moduli, the amount of crosslinker required in the former materials is higher. The evaporation of water and extra crosslinker add to the cost of the process. This problem is avoided by the present invention where a final drying step is generally not required.
Conventional crosslinking agents are used to provide the necessary mechanical stability and to control the adhesive properties of the composition. Typical crosslinkers include tripropylene glycol diacrylate, ethylene glycol dimethacrylate, alkoxylated triacrylate, polyethylene glycol diacrylate (PEG400 or PEG600), methylene bis acrylamide.
The aqueous reactive mixture optionally further comprises a surfactant, an additional monomer, an electrolyte, a processing aid (which is preferably a hydrophobic polymer), a water soluble polymer suitable for forming an interpenetrating polymer network, a non-hydrophilic polymer, an antimicrobial agent (e.g. citric acid, stannous chloride) and/or, for drug delivery applications, pharmaceutically active agents, the latter being designed to be delivered either passively (e.g. transdermally) or actively (e.g. iontophoretically) through the skin.
The process used to prepare bioadhesive compositions in accordance with the invention comprises mixing the ingredients to provide a reaction mixture in the form of an initial pre-gel aqueous based liquid formulation, which is then converted into a gel by a free radical polymerisation reaction. This may be achieved for example using conventional thermal initiators and/or photoinitiators or by ionizing radiation. Photoinitiation is a preferred method and will usually be applied by subjecting the pre-gel reaction mixture containing an appropriate photoinitiation agent to UV light after it has been spread or coated as a layer an siliconised release paper or other solid substrate. The processing will generally be carried out in a controlled manner involving a precise predetermined sequence of mixing and thermal treatment or history. One preferred feature of the process according to the invention is that no water is removed from the hydrogel after manufacture.